Control of Sleep and Wakefulness in Health and Disease - Progress in Molecular Biology and Translational Science - page 141

between LC firing and attention is like an inverted-U, 8 low firing (low nor-
adrenergic tone) being associated with inattentiveness, elevated firing (very
high noradrenergic tone) with highly labile attention, and firing between the
extremes with normal, focused attention. Attention deficit/hyperactivity
disorder (ADHD) is often treated with medications that increase noradren-
ergic tone (e.g., methylphenidate, D -/ L -amphetamine), effectively moving
people from inattentiveness to normal attention. It has been hypothesized
that a significant number of children who are diagnosed with ADHD are
misdiagnosed as such and are actually suffering from a disruption to their
sleep as caused by obstructive sleep apnea or insufficient sleep opportunity. 9
Reduction in sleep can cause the same type of inattentiveness and hyperac-
tivity (often referred to as paradoxical hyperactivity, as it is thought to be a
method by which the brain is attempting to rectify low noradrenergic tone
in the presence of or despite excessive sleepiness). Narcolepsy, a disease char-
acterized by a loss of hypocretin neurons (see below), is characterized by cat-
aplexy (loss of skeletal muscle tone in response to positive emotions such as
laughter) and a fundamental disruption of both wake and sleep consolida-
tion. 10 This disease is currently treated symptomatically. Individuals with
narcolepsy who are untreated have difficulty maintaining episodes of wake
for more than a few hours. 11 Current treatment involves the use of amphet-
amines and their derivatives, which primarily act by stimulating noradren-
ergic pathways. 12 Thus, when exogenously stimulated, the noradrenaline
system has the capacity to provide a substantial wake-promoting signal,
though the relative degree of contribution of endogenous noradrenaline
to wake promotion is likely much less. 13
Substantially, less research has been done into the role of dopamine in the
regulation of sleep and wake. Dopamine is generally considered a modulator
of motor function, but it is also involved in diverse brain functions such as
memory acquisition 14 and regulation of wake 15 among others. While an ini-
tial report indicated that mesencephalic dopamine neurons do not vary their
activity with sleep or wake state, 16 a more recent study indicates that at least
some of these neurons, specifically in the ventral periaqueductal gray matter,
are specifically wake active. 17 The loss of these dopamine-expressing neu-
rons in Parkinson's disease (PD) may help to explain the commonly
observed disruption of daytime wake in individuals with PD. 18 The disrup-
tion of wake in PD may precede observable motor disruption, 19 implying
either a progressive movement of the disease from wake-promoting dopa-
mine neurons to motor-modulating dopamine neurons or a varied threshold
at which wake and motor symptoms become evident. Dopamine is also